Ondansetron

Ondansetron is a Selective 5-HT₃ Receptor Antagonist belonging to an Antiemetic agent.

Ondansetron is a serotonin 5-HT3 receptor antagonist used to prevent nausea and vomiting in cancer chemotherapy and postoperatively.

Ondansetron is absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. Mean bioavailability in healthy subjects, following administration of a single 8-mg tablet, is approximately 56%. The volume of distribution of ondansetron has been recorded as being approximately 160L. The plasma protein binding associated with ondansetron was documented as approximately 73%. Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The metabolites are observed in the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation.

Ondansetron shows side effects like Headache, constipation, weakness, tiredness, chills, and drowsiness.

Ondansetron is available in the form of Oral Tablets, oral solutions, and Injectable solutions.

Ondansetron is available in India, the US, Canada, China, France, Italy, Russia, Spain, and Australia.

Ondansetron belongs to the Antiemetic agent and acts as a Selective 5-HT₃ Receptor Antagonist.

Ondansetron is a selective antagonist of the serotonin receptor subtype, 5-HT3. Cytotoxic chemotherapy and radiotherapy are associated with the release of serotonin (5-HT) from enterochromaffin cells of the small intestine, presumably initiating a vomiting reflex through stimulation of 5-HT3 receptors located on vagal afferents. Ondansetron may block the initiation of this reflex. Activation of vagal afferents may also cause a central release of serotonin from the chemoreceptor trigger zone of the area postrema, located on the floor of the fourth ventricle. Thus, the antiemetic effect of ondansetron is probably due to the selective antagonism of 5-HT3 receptors on neurons located in either the peripheral or central nervous systems, or both. Although the mechanisms of action of ondansetron in treating postoperative nausea and vomiting and cytotoxic-induced nausea and vomiting may share similar pathways, the role of ondansetron in opiate-induced emesis has not yet been formally established.

The Onset of action of Ondansetron is about 30 minutes.

The Tmax of Ondansetron is ~2 hours.

Ondansetron is a serotonin 5-HT3 receptor antagonist used to prevent nausea and vomiting in cancer chemotherapy and postoperatively.

Ondansetron is approved for use in the following clinical indications

Adult indication

• Carcinoid syndrome-associated diarrhea, severe, refractory
• Gastroparesis, a symptomatic treatment of nausea and vomiting
• Nausea and/or vomiting, acute, severe
• Postoperative nausea and vomiting, prevention
• Postoperative nausea and vomiting, treatment or rescue therapy
• Pregnancy-associated nausea and vomiting, severe or refractory
• Radiation therapy-associated nausea and vomiting, prevention
• Vertigo-associated nausea and vomiting

Pediatric indication

• Cyclic vomiting syndrome; treatment of an acute attack
• Gastroenteritis, acute; treatment
• Postoperative nausea and vomiting; prevention
• Radiation-induced nausea and vomiting, prevention

Adult Dose

• Carcinoid syndrome-associated diarrhea, severe, refractory

Oral: 8 mg 3 times daily or 8 mg twice daily for 3 days, followed by a maintenance dose of 4 to 8 mg/day for 4 to 12 weeks.

IV: 4 to 8 mg every 8 hours.

• Gastroparesis, is a symptomatic treatment of nausea and vomiting

Oral: 4 to 8 mg 3 times daily.

• Nausea and/or vomiting, acute, severe

Oral, IV, IM: 4 mg as a single dose

• Postoperative nausea and vomiting, prevention

Moderate- to high-risk patients

Usual dose: IV: 4 mg as a single dose at the end of surgery.

Alternative strategy: Oral (oral disintegrating tablet or oral soluble film): 8 mg as a single dose given 30 to 60 minutes prior to surgery.

Low-risk patients

Although prophylaxis is not always indicated in low-risk patients, consensus guidelines acknowledge that some experts may administer an antiemetic in these patients; however, clinicians are also advised that this strategy comes with the potentially unnecessary risk of rare adverse effects. If ondansetron is given, the dosing is the same as for moderate- to high-risk patients.

Post-discharge management in high-risk patients

Oral (oral disintegrating tablet or oral soluble film): 8 mg to be taken on discharge and in the morning of postoperative days 1 and 2.

• Postoperative nausea and vomiting, treatment, or rescue therapy

IV: 4 mg as a single dose when a prophylactic agent was not utilized (treatment) or following the failure of an agent utilized as prophylaxis (rescue therapy).

• Pregnancy-associated nausea and vomiting, severe or refractory

Patients without hypovolemia

Oral, IV (bolus): 4 mg every 8 hours, as needed, added to the current treatment regimen. If necessary, some experts increase to a maximum of 8 mg/dose.

Patients with hypovolemia

IV: 8 mg administered over 15 minutes every 12 hours, added to the current treatment regimen. Some experts use 4 to 8 mg administered as an IV bolus every 8 hours until stabilization

• Radiation therapy-associated nausea and vomiting, prevention

IV (off-label): 8 mg or 0.15 mg/kg (maximum: 16 mg/dose) once daily or twice daily prior to each fraction of radiation; administer in combination with dexamethasone.

Oral: 8 mg once daily or twice daily administered 1 to 2 hours prior to each fraction of radiation; administer in combination with dexamethasone or, in one clinical trial of 4 days of hyper fractionated total body irradiation, 8 mg (without dexamethasone) was administered 1.5 hours prior to every fraction of radiation (3 times daily for the first 3 days and twice daily on day 4).

• Vertigo-associated nausea and vomiting

IV (preferred), IM: 4 to 8 mg once for acute symptoms.

Oral: 4 mg every 8 to 12 hours as needed

Pediatric Dose

• Cyclic vomiting syndrome; treatment of an acute attack

Children >2 years and Adolescents:

Low dose: IV: 0.15 mg/kg every 4 hours as needed for up to 3 doses; maximum dose: 16 mg/dose.

High dose: IV: 0.3 to 0.4 mg/kg/dose every 4 to 6 hours; maximum dose: 16 mg/dose; should not exceed 3 doses in a 24-hour period.

• Gastroenteritis, acute; treatment

IV: Infants and Children: IV: 0.15 or 0.3 mg/kg/dose once; maximum dose: 16 mg/dose.

Oral: Infants ≥6 months and Children ≤10 years, weighing ≥8 kg.

8 to 15 kg: Oral: 2 mg/dose once.

>15 to 30 kg: Oral: 4 mg/dose once.

>30 kg: Oral: 8 mg/dose once.

• Postoperative nausea and vomiting; prevention

Infants and Children:

≤40 kg: IV: 0.1 mg/kg/dose as a single dose; maximum dose: 4 mg/dose.

>40 kg: IV: 4 mg/dose as a single dose.

Adolescents: IM, IV: 4 mg/dose as a single dose.

• Radiation-induced nausea and vomiting, prevention

Fixed dose:

Children 4 to 11 years: Oral: 4 mg every 8 hours throughout Traumatic brain injury (TBI) prior to hematopoietic stem cell transplant (HSCT).

Children ≥12 years and Adolescents: Oral: 8 mg every 8 hours throughout TBI prior to HSCT.

Alternate fixed dosing:

Children ≥9 years and Adolescents: Oral: 8 mg every 12 hours on days of TBI prior to bone marrow transplantation (age range: 9 to 67 years; median age range: 39 to 49 years).

Ondansetron is available in various strengths as 4 mg/5 mL; 32 mg/50 mL-D5%; 2 mg/mL; 4 mg; 8 mg; 24 mg; 32 mg/50 mL-NaCl 0.9%

Ondansetron is available in the form of Oral Tablets, oral solutions, and Injectable solutions.

• Dosage Adjustment in Kidney Patient

Altered kidney function: IV, Oral: No dose adjustments likely to be necessary, as clearance by the kidney accounts for only 5% of total clearance (Roila 1995; manufacturer’s labeling). Unlikely to be significantly dialyzed due to the relatively high volume of distribution and plasma protein binding

• Dosage Adjustment in Hepatic impairment Patient

Mild to moderate impairment: No dosage adjustment necessary.

Severe impairment (Child-Pugh class C):

IV: Day 1: Maximum daily dose: 8 mg; however, according to the manufacturer, there is no experience beyond first-day administration (has not been studied beyond day 1)

Oral: Maximum daily dose: 8 mg

Ondansetron is contraindicated in patients 

• known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any of the components of the formulation.
• receiving concomitant apomorphine due to the risk of profound hypotension and loss of consciousness

• Serotonin syndrome

Serotonin syndrome (SS) has been reported with 5-HT₃ receptor antagonists, predominantly when used in combination with other serotonergic agents (eg, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and/or methylene blue). Some of the cases have been fatal. The majority of serotonin syndrome reports due to 5-HT₃ receptor antagonists have occurred in a post-anesthesia setting or in an infusion center. SS has also been reported following an overdose of ondansetron. Signs/symptoms of SS include mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile BP, diaphoresis, dizziness, flushing, hyperthermia); neuromuscular changes (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures.

• Benzyl alcohol and derivatives

Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse some data suggests that benzoate displaces bilirubin from protein binding sites avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates.

• Phenylalanine

Orally disintegrating tablets contain phenylalanine.

• Chemotherapy-associated emesis

Antiemetics are most effective when used prophylactically. If emesis occurs despite optimal antiemetic prophylaxis, re-evaluate emetic risk, disease status, concurrent morbidities, and current medications to assure the antiemetic regimen is optimized.

It is not known whether ondansetron is present in human milk. There are no data on the effects of Ondansetron on the breastfed infant or the effects on milk production. However, it has been demonstrated that ondansetron is present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Ondansetron and any potential adverse effects on the breastfed infant from Ondansetron or from the underlying maternal condition.

Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Common

● Constipation, Fatigue, headache, malaise, Pruritus, skin rash, Diarrhea, Gynecologic disease, urinary retention, Increased serum alanine aminotransferase, increased serum aspartate aminotransferase, Anaphylaxis, Injection site reaction Agitation, anxiety, dizziness, drowsiness, paresthesia, sedated state, the sensation of cold, Bronchospasm, hypoxia, Fever.

Rare

● Hypotension, Extrapyramidal reaction, Angina pectoris, peripheral vascular disease, tachycardia, Hypokalemia, Tonic-clonic epilepsy, Atrial fibrillation, bradycardia, depression of ST segment on ECG, flushing, ischemic heart disease (most commonly due to coronary artery spasm and may occur with oral or IV [predominantly IV]; occurred immediately after IV administration and resolved with treatment), palpitations, prolonged QT interval on ECG, second-degree atrioventricular block, supraventricular tachycardia, syncope, torsades de pointes, ventricular premature contractions, ventricular tachycardia, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, Hiccups, intestinal obstruction, Positive lymphocyte transformation test, Hepatic failure, Angioedema, fixed drug eruption, hypersensitivity reaction, nonimmune anaphylaxis, Dystonic reaction, serotonin syndrome, Laryngospasm.

• Serotonergic Drugs

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue Ondansetron and initiate supportive treatment.

• Drugs Affecting Cytochrome P-450 Enzymes

Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for Ondansetron is recommended for patients on these drugs.

• Tramadol

Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small trials indicate that when used together, Ondansetron may increase patient-controlled administration of tramadol. Monitor patients to ensure adequate pain control when ondansetron is administered with tramadol.

• Chemotherapy

Carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover trial in 76 pediatric patients, intravenous ondansetron did not increase systemic concentrations of high-dose methotrexate.

• Alfentanil and Atracurium

Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the degree of neuromuscular blockade produced by atracurium. Interactions with general or local anesthetics have not been studied.

The common side effects of Ondansetron include the following

Common side effects

● Headache, constipation, weakness, tiredness, chills, drowsiness.

Rare side effects

● Blurred vision or vision loss, rash, hives, itching, swelling of the eyes, face, lips, tongue, throat, hands, feet, ankles, or lower legs, hoarseness, difficulty breathing or swallowing, chest pain, shortness of breath, dizziness, light-headedness, or fainting, fast, slow or irregular heartbeat, agitation, hallucinations, fever, excessive sweating, confusion, nausea, vomiting, or diarrhea, loss of coordination, stiff or twitching muscles, seizures, coma (loss of consciousness).

• Pregnancy

Pregnancy Category B

Available data do not reliably inform the association between Ondansetron and adverse fetal outcomes. Published epidemiological studies on the association between ondansetron and fetal outcomes have reported inconsistent findings and have important methodological limitations hindering interpretation. Reproductive studies in rats and rabbits did not show evidence of harm to the fetus when ondansetron was administered during organogenesis at approximately 6 and 24 times the maximum recommended human oral dose of 24 mg/day, based on body surface area, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

• Nursing Mothers

It is not known whether ondansetron is present in human milk. There are no data on the effects of Ondansetron on the breastfed infant or the effects on milk production. However, it has been demonstrated that ondansetron is present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Ondansetron and any potential adverse effects on the breastfed infant from Ondansetron or from the underlying maternal condition.

• Pediatric Use

The safety and effectiveness of orally administered Ondansetron have not been established in pediatric patients for:

• Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy.
• Prevention of nausea and vomiting associated with radiotherapy.
• Prevention of postoperative nausea and/or vomiting.

• Geriatric Use

Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US- and foreign-controlled clinical trials, for which there were subgroup analyses, 938 (19%) were aged 65 years and older. No overall differences in safety or effectiveness were observed between subjects 65 years of age and older and younger subjects. A reduction in clearance and an increase in elimination half-life were seen in patients older than 75 years compared with younger subjects. There were an insufficient number of patients older than 75 years of age and older in the clinical trials to permit safety or efficacy conclusions in this age group. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment is needed in elderly patients.

There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. In addition to the adverse reactions listed above, the following adverse reactions have been described in the setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 2 to 3 minutes duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in a patient that took 48 mg of Ondansetron tablets. Following an infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. In all instances, the adverse reactions resolved completely. Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeding the estimated ingestion of 5 mg per kg) in young children. Reported symptoms included somnolence, agitation, tachycardia, tachypnea, hypertension, flushing, mydriasis, diaphoresis, myoclonic movements, horizontal nystagmus, hyperreflexia, and seizure. Patients required supportive care, including intubation in some cases, with complete recovery without sequelae within 1 to 2 days.

Pharmacodynamic

Ondansetron is a highly specific and selective serotonin 5-HT₃ receptor antagonist, not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors. The serotonin 5-HT₃ receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema. The temporal relationship between the emetogenic action of emetogenic drugs and the release of serotonin, as well as the efficacy of antiemetic agents, suggest that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT₃ receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting.

Pharmacokinetics

• Absorption

Ondansetron is absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. Mean bioavailability in healthy subjects, following administration of a single 8-mg tablet, is approximately 56%. Ondansetron systemic exposure does not increase proportionately to dose. The AUC from a 16-mg tablet was 24% greater than predicted from an 8-mg tablet dose. This may reflect some reduction of first-pass metabolism at higher oral doses.

• Distribution

The volume of distribution of ondansetron has been recorded as being approximately 160L. The plasma protein binding associated with ondansetron was documented as approximately 73%.

• Metabolism and Excretion

Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The metabolites are observed in the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation. In vitro metabolism, studies have shown that ondansetron is a substrate for human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall rates of ondansetron elimination. Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020103s035_020605s019_020781s019lbl.pdf
• https://www.uptodate.com/contents/ondansetron-drug-information?search=ondansetron-drug-&source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1
• https://reference.medscape.com/drug/Ondansetron -zuplenz-ondansetron-342052#0
• https://medlineplus.gov/druginfo/meds/a601209.html
• https://www.drugs.com/dosage/ondansetron.html
• https://www.rxlist.com/Ondansetron -drug.htm#clinpharm
• https://www.mims.com/india/drug/info/ondansetron?type=full&mtype=generic
• https://go.drugbank.com/drugs/DB00904
• https://www.practo.com/medicine-info/ondentron-4-mg-tablet-8066#:~:text=It is used for the,that causes nausea or vomiting.